Fas enhances fibrogenesis in the bile duct ligated mouse

A link between apoptosis and fibrosis

Ali Canbay, Hajime Higuchi, Steven F. Bronk, Makiko Taniai, Tom J. Sebo, Gregory James Gores

Research output: Contribution to journalArticle

220 Citations (Scopus)

Abstract

Background & Aims: Hepatocyte apoptosis and fibrosis are both features of liver injury. However, the potential mechanistic link between these 2 processes remains obscure. Our aim was to ascertain if Fas-mediated hepatocyte apoptosis promotes liver fibrogenesis during extrahepatic cholestasis. Methods: Wild-type and Fas-deficient lymphoproliferation (Ipr) mice underwent bile duct ligation. Liver injury was assessed by quantitating hepatocyte apoptosis with the terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay and determining serum ALT values. mRNA expression was quantitated using real-time polymerase chain reaction technology. Liver fibrosis was assessed by digital image analysis of Sirius red-stained sections. Results: In 3-day bile duct ligated (BDL) animals, TUNEL-positive hepatocytes and serum ALT values were reduced in Ipr versus wild-type animals. Likewise, hepatic mRNA transcripts for α-smooth muscle actin and platelet-derived growth factor receptor-β (initiation phase of stellate cell activation) and transforming growth factor β1 mRNA, collagen 1α, and tissue inhibitor of matrix metalloproteinases (perpetuation phase of stellate cell activation) were also reduced in 3-day BDL wild-type mice compared with Ipr mice. Finally, in 3-week BDL mice, immunoreactivity for α-smooth muscle actin and Sirius red staining for collagen were significantly less in Ipr compared with wild-type animals. Conclusion: Fas-mediated hepatocyte injury is mechanistically linked to liver fibrogenesis. These observations suggest that inhibition of Fas-mediated apoptosis may be a therapeutic antifibrogenic strategy in cholestatic liver diseases.

Original languageEnglish (US)
Pages (from-to)1323-1330
Number of pages8
JournalGastroenterology
Volume123
Issue number4
DOIs
StatePublished - Oct 1 2002

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Bile Ducts
Hepatocytes
Fibrosis
Apoptosis
Liver
Wild Animals
Transferases
Messenger RNA
Smooth Muscle
Actins
Wounds and Injuries
Collagen
Extrahepatic Cholestasis
Platelet-Derived Growth Factor Receptors
Tissue Inhibitor of Metalloproteinase-1
Transforming Growth Factors
Serum
Liver Cirrhosis
Ligation
Liver Diseases

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Fas enhances fibrogenesis in the bile duct ligated mouse : A link between apoptosis and fibrosis. / Canbay, Ali; Higuchi, Hajime; Bronk, Steven F.; Taniai, Makiko; Sebo, Tom J.; Gores, Gregory James.

In: Gastroenterology, Vol. 123, No. 4, 01.10.2002, p. 1323-1330.

Research output: Contribution to journalArticle

Canbay, Ali ; Higuchi, Hajime ; Bronk, Steven F. ; Taniai, Makiko ; Sebo, Tom J. ; Gores, Gregory James. / Fas enhances fibrogenesis in the bile duct ligated mouse : A link between apoptosis and fibrosis. In: Gastroenterology. 2002 ; Vol. 123, No. 4. pp. 1323-1330.
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